ABSTRACT The development of the majority of breast cancers (BrCAs) is largely influenced by non-genetic factors such as high fat diet (HFD) induced obesity. The pathophysiological mechanisms that link HFD-induced obesity to BrCA risk include inflammatory processes; adipose tissue macrophages (M-Phi-s) are primary contributors to inflammation however there has been no systematic evaluation of their specific role in HFD-enhanced BrCA. Dietary compounds are of interest given their low toxicity profiles and their ability to target inflammation; however there is a fundamental gap in the understanding of their effectiveness and their mechanism(s) of action in HFD-enhanced BrCA. The long-term goal is to develop the anti-inflammatory flavonoid quercetin as a clinically testable dietary regimen to delay and/or prevent HFD-enhanced BrCA. The objective in this particular investigation is to evaluate whether M-Phi-s are a target for the anti-inflammatory effects of quercetin in HFD-enhanced BrCA and to determine if these effects are mediated through sirtuin 1 (SIRT1). The central hypothesis is that the mechanism of action of quercetin on the regulation of M-Phi-induced inflammation in HFD-enhanced BrCA is mediated through SIRTL This hypothesis has been formulated on the basis of several converging lines of evidence from the applicants' laboratory. The rationale for the proposed research is that elucidating the targets of quercetin and their mechanism of action in the regulation of these targets will translate to a more effective prevention/treatment approach in HFD-enhanced BrCA. This hypothesis will be tested by pursuing three specific aims: 1) Elucidate the stage-specific effects of quercetin on inflammation in HFD-enhanced BrCA; 2) Evaluate whether M-Phi-s are a target for the anti-inflammatory effects of quercetin in HFD-enhanced BrCA; and 3) Determine whether SIRT 1 is a mediator of the effects of quercetin in the regulation of M-Phi-induced inflammation in HFD-enhanced BrCA. Under the first aim, the C3(1)SV40Tag mouse model of BrCA, that will be fed a HFD to induce obesity, will be used to determine the stage-specific effects of quercetin on inflammation and subsequent tumorigenesis and overall survival. Under the second aim, in vivo M-Phi manipulation techniques will be used such as crossing the C3(1)Tag transgenic mouse model of BrCA with a MCP-1 knockout mouse to generate a M-Phi deficient mouse model of BrCA. This will help determine the role of M-Phi-s on the benefits of quercetin in HFD-enhanced BrCA. Finally, under aim 3, SIRT1 manipulation techniques will be used to examine the role of SIRT1 as a mediator of the effects of quercetin on M-Phi-induced inflammation in HFD-enhanced BrCA. The innovation of the proposed investigation is anchored in the examination of SIRT1 as a mediator of the benefits of the bioactive dietary component quercetin in the regulation of M-Phi-induced inflammation in HFD-enhanced BrCA. The proposed investigation is significant as it addresses prevention of incidence and progression of HFD-enhanced BrCA by using a dietary food component to target inflammation that is at the mechanistic core of this disease.